About this Author

College chemistry, 1983

The 2002 Model

After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases.
To contact Derek email him directly: derekb.lowe@gmail.com
Twitter: Dereklowe

September 9, 2010

PLX4032: The Good News and the Bad News

Posted by Derek

There's been a lot of excitement about PLX4032, which has shown some dramatic effects against late-stage melanoma. Very few therapies have done anything at all in that patient population, so on that level, the excitement is justified.

The compound is an azaindole targeting a mutated form (V600E, that is, glutamate for valine at amino acid 600) of B-RAF, a well-known cancer kinase target. The compound seems to be very selective indeed for this form, with no significant activity at wild-type RAF or other kinases (That glutamic acid makes all the difference). Update - that's overstating the case; see the comments section). A significant proportion of melanoma cases show this mutation, as it turns out.

Testing it out in the clinic has not been easy. As this Nature News piece details, one key was to come up with a better formulation than the original one. I can well believe it - azaindole kinase inhibitors are not the most tractable molecules on the planet, and PLX4032 doesn't look any less like a brick than the rest of 'em. (Update: fixed link to structure). The initial trials were done with crystalline material, which I'll bet doesn't dissolve worth a hoot, but the later runs were done with some sort of microprecipitated powder, which seems to behave better. They managed to get up to 720mg b.i.d., which is the sort of load you associate with antibiotics and similar horse pills, before dose-limiting tox set in.

Most of the patients in the study had the V600E mutation; the few that didn't showed no effects whatsoever. (And yes, this is an ethical study, because the standard of care for late-stage melanoma consists of everyone standing around wringing their hands). But of the group with the mutation, about 4/5ths of them showed partial or complete regression, which is unheard of.

Here's the bad news: that regression doesn't last. Of the people who responded to the drug, that response lasted from 2 to around 18 months. (And keep in mind, there were people with the mutation who also showed no response at all, for reasons that are totally unclear). What seems to be happening is either the tumor cells are mutating around the effect of PLX4032, coming up with yet another B-RAF variation, or there could be some cells around from the start that escape its effects (and then take over). We don't have survival data yet, but the best guess is that the drug will add a few months to the lives of these patients. It's not a cure, and that's the bad news.

But on the other hand, it's the first time anything has done much of anything for such patients. If we can find out why some of the V600E tumors don't respond, or better characterize the ones that re-occur after treatment, that could point the way to something more significant. That's not going to be easy - but it's not impossible, either. It's a start, for sure.

"The compound seems to be very selective indeed for this form, with no significant activity at wild-type RAF or other kinases."

That's not true. The compound has ~5-fold selectivity for mutant over WT Raf, and inhibits a few other kinases at low nanomolar concentrations.

Patients achieve a mean plasma concentration of 86 micromolar after two weeks on PLX4032. That's incredibly high. This drug is inhibiting dozens if not hundreds of kinases at that concentration. That's not to say that the therapeutic response does not require b-Raf inhibition -- of course it does -- but there could be something else going on as well.

At 100s of micromolar, aren't there significant off target effects and therefore lots of side effects? most certainly wt braf is being hit and multipel pathways including some important ones are being shut down.

The pattern of tumor re-emergence would suggest that it's not a mutational mechanism. If you've got 50 mets, this compound can regress them all to near invisible, but they all come back in the exact same spots. That implies that the adaptation to resist the treatment must be pretty easy/common, so we probably aren't talking about a specific kinase domain mutation or anything. If that were the mechanism, I would expect more of a jackpot effect where some of the mets come back but not others. I bet this is something like epigenetic de-regulation of CRAF or something similar.

Zack, PLX4032 is a very selective drug, probably more selective than other ATP-competive kinase inhibitor in late stage trials/on the market. The protein binding of this drug is extremey high so there isn't much free drug around which in part explains the high plasma concentrations needed. Nobody knows for sure, but I doubt that inhibition of other kinases plays a significant role, at least not to the extent that it does for other approved kinase inhibitors. Derek, part of the high B-Raf V600E "selectivity" is explained by the KM(ATP). The V600E isoform has a ~12-fold lower ATP affinity than wildtype-B-Raf and C-Raf.

11. small but perfectly formed on September 10, 2010 7:25 AM writes...

It is my opinion that I may well have heard the story of the microprecipitated bulk powder (MBP) formulation of this stuff from a Roche delegate at the EFMC-ISMC 2010 Symposium in Brussels on the 8th of September.

He described the compound as a 'brick dust like oncology compound from a US based biotech' and they did not consent to him disclosing the compound code or structure.

... and I have to say, a truly fascinating story (complete with a MBP manufacturing video) it was too.

All these big name R&D heads still do not get it. Cancer cells are not homogeneous. Cancer should be treated as a viral disease. Both are characterized by the low fidelity in replication. Hence, the high mutation rate. Many mutants exist in a single cancer cluster. Some mutants are fitter than the other but the dominant mutant does not wipe out the other mutants. When the dominant mutant is killed by a targeted drug, the other mutants simply get more room to proliferate. In order to cure cancer, not just delaying the progression, the drugs need to kill all cancer mutants quickly. Just like AIDS therapy, it takes a combination of drugs blocking all the essential processes for replication. The biggest challenge is that cancer cells shared most replication processes with normal cells. It is our job to sort out the differences and come up with a cure. It is really unethical to market a "cancer drug" which delay the progression for a few weeks and charge the patients all their saving.

It is our job to sort out the differences and come up with a cure.
Actually, the goal of cancer treatment is to ensure that the patient dies of something else first. For example, if you can delay death by prostate cancer by 5 years, a lot of those men will die of cardiac disease instead. That goes in the win column as far as treating their cancer is concerned.

It is really unethical to market a "cancer drug" which delay the progression for a few weeks and charge the patients all their saving.
No, it's silly of the patients to buy such a drug.

The problem with medications like these is the fact that they are marketed so well and that families of cancer patients are so desperate that they'd spend all what they have for any glimpse of hope. Chemotherapy/Radiotherapy is the only real way to get rid of cancer atm, and big industries are focusing on profits instead of making a real cure. I'm sure that this tablet will cost a lot when it is released- you can just tell by the way its marketed on the web. Commercial shit. Let's focus instead on working towards a real cure for cancer and its likes and let's make any product we come up with affordable, because stealing off burnt families is no real accomplishment.

Most people would consider an extra year of (reasonably healthy) life worth quite a lot. So if this thing hits the snooze button for several months or more, people quite rationally might want to buy it even if the alarm is still going to go off shortly thereafter.

Just stumbled onto this thread, not a medical professional here. Trying to find some treatments for my 33yr old girlfriend with stage IV melanoma. She was on Interferon for a solid month in September, but by late November, lesions on her lung, liver, omentum, and right grown lymphnodes. She is getting treatment at the Los Angeles County hospital now, not the best of course. No idea which clinical trial would be best for her. Seen good things with Oncovex in phase III trial, also Ipilimumab trials at Dana Farber. This PLX4032 may just be a short life extender.

Would love some input from doctors, researchers, or anyone with some insight. I can be reached at gazin@sbcglobal.net.

This is an amazing young woman who would impress anyone with her intelligence, humor, courage and dignity. I know there are no miracles with Melanoma, but if there were, she would be one worthy of receiving.

I had metastatic malignant melanoma. Was treated by Steven Rosenberg at NCI /NIH with high dose IL2 and GP100.
I am now 12 years out since last evidence of disease. The team at NCI /NIH seemed then and probably still do more than wring their hands about cases of metastatic malignant melanoma. What are your thoughts about what they have done and are doing?
Thanks very much.

I had metastatic malignant melanoma. Was treated by Steven Rosenberg at NCI /NIH with high dose IL2 and GP100.
I am now 12 years out since last evidence of disease. The team at NCI /NIH seemed then and probably still do more than wring their hands about cases of metastatic malignant melanoma. What are your thoughts about what they have done and are doing?
Thanks very much.

I had metastatic malignant melanoma. Was treated by Steven Rosenberg at NCI /NIH with high dose IL2 and GP100.
I am now 12 years out since last evidence of disease. The team at NCI /NIH seemed then and probably still do more than wring their hands about cases of metastatic malignant melanoma. What are your thoughts about what they have done and are doing?
Thanks very much.

My husbands melanoma recently reoccurred and in a matter if weeks has spread throughout his body. He has unndergone radiation to the brain and as a result the doctors tell us he is not eligible to be included in any clinical trials. Is this true and is there anyone we can contact to discuss quickly. Time is of the essence. Atthis time they tell us his only option is Tremador.

First not at medical type, just a person with a disease.
Started off in December 2010 and January 2011 with surgery. About 1 year later (January 2012) I had a reoccurenace. After a short try of chemo the melanoma was demonstrating it's aggressiveness and was spreading quickly . Fortunately the disease was not in the organs, brain or bone. The doctor got me on a trial of Ipilimumab and that stopped the spread of the disease (still had tumours but they were shrinking). While waiting for the next round of Ipilimumab, the doctor wanted to try the PLX4032 since I had the V600E mutation. Currently on day 5 of the drug and a few of the tumours are starting to shrink. I want to finish this round of PLX4032 and then go back onto the Ipilimumab.
I know this probably won't cure me, but if I can buy time, the researchers and medical profession may discover a cure.
The Ipilimumab study was NCT00495066 see websitehttp://ctr.bms.com/OneBmsCtd/InitTrialAction.do?linkname=Cancer&type=pharma&sortby=default.

My advice: Enjoy each extra day you are given.

I hope this helps someone. In Canada there is a melanoma network (see www.melanomanetwork.ca).

There were several questions higher in this thread on cost.
After the doctor prescribed the drug, a case worker from Roche Patient Assistance Program called me and asked the usual questions (what other medicines are your taking etc). Before I supplied my insurance company contact information, the case worker said they would make sure if the insurance company didn't cover it or you didn't have coverage, Roche would cover the costs and no one would be turned away due to not being able to cover the cost. Fortunately, my insurance company takes care of these kinds of things and between the insurance and Roche I didn't pay anything. The cost was CDN$9,500 for 21 day supply. 4 tablets in the morning and 4 in the evening.